Effectiveness of the adapted bivalent mRNA COVID-19 vaccines against hospitalisation in individuals aged ≥ 60 years during the Omicron XBB lineage-predominant period: VEBIS SARI VE network, Europe, February to August, 2023

We conducted a multicentre hospital-based test-negative case–control study to measure the effectiveness of adapted bivalent COVID-19 mRNA vaccines against PCR-confirmed SARS-CoV-2 infection during the Omicron XBB lineage-predominant period in patients aged ≥ 60 years with severe acute respiratory infection from five countries in Europe. Bivalent vaccines provided short-term additional protection compared with those vaccinated > 6 months before the campaign: from 80% (95% CI: 50 to 94) for 14–89 days post-vaccination, 15% (95% CI: −12 to 35) at 90–179 days, and lower to no effect thereafter.

We conducted a multicentre hospital-based test-negative case-control study to measure the effectiveness of adapted bivalent COVID-19 mRNA vaccines against PCR-confirmed SARS-CoV-2 infection during the Omicron XBB lineage-predominant period in patients aged ≥ 60 years with severe acute respiratory infection from five countries in Europe.Bivalent vaccines provided short-term additional protection compared with those vaccinated > 6 months before the campaign: from 80% (95% CI: 50 to 94) for 14-89 days post-vaccination, 15% (95% CI: −12 to 35) at 90-179 days, and lower to no effect thereafter.

Vaccine effectiveness study design and patient selection
The methodology of the Vaccine Effectiveness, Burden and Impact Studies (VEBIS) project hospital vaccine effectiveness (VE) study has been described elsewhere [4].It is a hospital-based, multicentre, case-control study with a test-negative design, including > 50 hospitals at 12 sites in 11 participating European countries (two sites in Spain) (Figure 1) [4].
Patients with SARI were individuals hospitalised for ≥ 24 h with at least one of the following symptoms: fever, cough, shortness of breath or sudden onset of anosmia, ageusia or dysgeusia [5].Cases and controls were SARI patients that tested positive and negative for SARS-CoV-2 by PCR, respectively, within 48 h of admission or in the previous 14 days.
The XBB lineage-predominant period was defined for each country as the timeframe when the proportion of XBB lineage or XBB.1.5 or XBB.1.5+ F456L sub-lineages among sequenced samples reported to Global Initiative on Sharing All Influenza Data (GISAID) or to The European Surveillance System (TESSy) [6] was above 60%.The final study period comprised records between 15 February and 31 August 2023.Exclusion criteria and the restriction flowchart are available in Supplementary Figure S1.

SARI patient description
During our study period, we included 743 cases and 3,045 controls aged ≥ 60 years, from 31 European hospitals, in six participating study sites (Figure 1).
Of the total, 70% of cases (n = 518) and 66% of controls (n = 2,012) were vaccinated with a bivalent booster, while 30% (n = 225) of cases and 34% (n = 1,033) controls had not received a bivalent booster but had at least one monovalent vaccine more than 6 months before the start of the bivalent vaccines roll-out (Table 1).Among SARI patients vaccinated with a bivalent vaccine, 90% of cases (n = 466) and 87% of controls (n = 1,746) had received two booster doses.Among SARI patients that did not receive a bivalent vaccine, 82% of cases (n = 184) and 81% of controls (n = 833) had received one booster dose (Table 1).Seventythree percent of cases (n = 377) and 59% of controls (n = 1,181) with a bivalent booster during the XBB lineage period were vaccinated more than 180 days before symptom onset (Table 1).The median time since vaccination for those vaccinated with a bivalent booster was 215 (IQR: 176-274) days for cases and 193 (IQR: 154-241) days for controls (Table 1).

Effectiveness of bivalent COVID-19 mRNA vaccines
The number of doses and the last vaccination date were used as a proxy to identify the vaccine valency (bi-or monovalent), based on the introduction date of the bivalent vaccines provided by each country (data not shown).
We estimated relative VE (rVE) and incremental VE (iVE), where we applied different vaccination status definitions for the assessment of the vaccine effectiveness (Table 2).We decided not to use never-vaccinated individuals as a reference group, as they have become a smaller group over time, and were not eligible to receive a booster dose during the bivalent vaccine campaign.Patients vaccinated 1-13 days before symptom onset were excluded.Effectiveness was analysed by time since vaccination (TSV) using 60-and 90-day bands.
We estimated the odds ratio (OR) of vaccination using a logistic regression model adjusted for date of symptom onset, study site, sex, age and presence of a chronic condition.We carried out a complete case analysis.
The VE was calculated as (1−OR) x 100%.Estimates were not shown if there were fewer than 20 vaccinated patients, fewer than five vaccinated/unvaccinated cases or controls, or when the estimate had an absolute difference > 10% from that found from using penalised logistic regression (to assess small sample bias).

Discussion
Our results suggest that the adapted bivalent mRNA COVID-19 vaccines conferred additional protection during the XBB-predominant period compared with those vaccinated with at least primary series vaccination more than 6 months before the bivalent vaccination campaign.We observed a decline in effectiveness, from 80% rVE in the first 89 days to 15% at 90-179 days, and no effect at 270-359 days.Similar results were found for iVE.This is likely due to the overlap of the study populations, as 87% of those who received a bivalent booster had received this as their second booster dose, and 80% of those vaccinated more than 6 months before the start of the campaign had only received a first booster dose of a monovalent COVID-19 vaccine.
The decline of bivalent VE over time against hospitalisation during the XBB period has also been reported by other studies [7][8][9].Our VE estimates are consistent with their results, with slightly higher VE point estimates for the more recent vaccinations (up to 119 days).
Our study had, however, a smaller sample size for the shorter time since vaccination.
It is challenging to disentangle waning immunity from changes in viral circulation as well as from depletion of susceptible individuals.Although restricting the analysis to the XBB-predominant period, the proportion of XBB-related sub-lineages increased over time, being the lowest at the start, with the underlying XBB sub-lineage also varying over time (XBB, XBB.1.5 and XBB.1.5+ F456L).Five sites sequenced 274 (31%) SARS-CoV-2-positive samples during the analysis period and, of these, 88% were identified as XBB.
Previous results from our VEBIS SARI VE network for a monovalent booster during the Omicron-dominant period showed ≥ 70% VE up until 120 days in those aged ≥ 60 years [10].Since vaccines were not administered in the same period, it is difficult to make direct  a Relative VE (rVE) compared those vaccinated with any bivalent booster dose ('vaccinated') with those not vaccinated with a bivalent vaccine but vaccinated with at least primary series vaccination, received > 6 months before the bivalent campaign start ('unvaccinated').Vaccine valency (bi-or monovalent) was defined based on the date of the introduction of the bivalent vaccines in each country.
b Incremental VE (iVE) compared those vaccinated with primary series vaccination plus two booster doses, with the second booster being a bivalent vaccine ('vaccinated'), with those vaccinated with primary series vaccination plus one monovalent booster dose, received > 6 months before the bivalent campaign start ('unvaccinated').Vaccine valency (bi-or monovalent) was defined based on the date of the introduction of the bivalent vaccines in each country.comparisons.In addition to different virus circulation, the immunological landscape and exposure risk of the population has also changed over time, with the lifting of non-pharmaceutical measures previously in place and with a high primary series vaccination coverage during our study period [11].The findings from our analysis should be interpreted in the context of this underlying immunity as the additional protection provided by the bivalent vaccination.
Our study has limitations.Firstly, the autumn 2022 bivalent vaccination campaign took place roughly 6 months before the predominance of XBB in participating countries, reflected in the long median time since vaccination in both cases and controls and in the small sample size for VE estimates for those with more recent vaccinations.Additionally, patient recruitment decreased during the summer, following the decrease of SARI incidence, reflected in the relatively small sample size during the XBB-dominated period.Secondly, we did not adjust for previous SARS-CoV-2 infection, as this is not collected by all sites.This could lead to underestimation of VE, if prior infection is negatively associated with vaccination e.g. if the recently infected are less likely or ineligible to be vaccinated.However, some studies have reported no differences when controlling for previous infection [12].Thirdly, the analyses were conducted assuming that (i) all booster doses taken after the roll-out of the bivalent vaccines in each country were either bivalent Original/Omicron BA.1 or Original/Omicron BA.4-5; and (ii) the COVID-19 variant causing the infection and subsequent hospitalisation were XBB (XBB, XBB.1.5 or XBB.1.5+ F456L) based on time when these sub-lineages predominated; introducing risk of misclassification of both outcome and exposure of interest.
There are many strengths of our multicentre study.We are able to include data from several countries and sites, which allows us to have a larger sample size and to cover a diverse population across Europe, to have a pooled VE estimate that might be more generalisable.
In addition, sites participating in the network follow a generic protocol, which helps to mitigate potential sources of heterogeneity.

Conclusions
The findings of our study suggest that the bivalent vaccines provided short-term additional protection against hospitalisation among those aged ≥ 60 years during the XBB predominant period.

License, supplementary material and copyright
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This article is copyright of the authors or their affiliated institutions, 2024.

Figure 1
Figure 1Countries and sites participating in the VEBIS SARI VE network, Europe, 2023

Figure 2
Figure 2 Bivalent COVID-19 relative a and incremental b vaccine effectiveness against hospitalisation among SARI patients aged ≥ 60 years by time since vaccination (A) 90-day bands and (B) 60-day bands, VEBIS SARI VE network, Europe, XBB lineage predominant period, 15 February-31 August 2023

Table 1
SARI patient characteristics by case and control status, VEBIS SARI VE network, Europe, 15 February-31 August 2023 (n = 3,788) Monovalent At least one of five commonly collected conditions, i.e. diabetes, heart disease, lung disease, asthma and immunodeficiency.b Admission to an intensive care unit (ICU), use of respiratory support such as mechanical ventilation or extra-corporeal membrane oxygenation (ECMO) or death.
Vaccination status and dose at time of symptom onsetBivalent booster (received during the bivalent vaccination campaign) vaccine (> 6 months before the start of the bivalent vaccination campaign)IQR: inter-quartile range; SARI: severe acute respiratory infection; VE: vaccine effectiveness; VEBIS: Vaccine Effectiveness, Burden and Impact Studies.a